Post on 17-Aug-2020
Clinical Activity with Brentuximab Vedotin in
Cutaneous T-cell Lymphoma
- Updated analysis -
- Time to next treatment -
- Disease Stages/Compartments -
- CD30 Expression Level -
Disclosures
Co-funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary
of Takeda Pharmaceutical Company Limited, and Seattle Genetics, Inc., Bothell, WA, USA
H. Miles Prince: Advisory board member for Millennium/Takeda Pharmaceuticals; has received
honoraria for advisory boards and research funding for clinical trials
Full disclosure information for all authors is available on request
Brentuximab vedotin was far superior to physician’s choice, demonstrating improved ORR4 (56% vs 13%; p<0.0001),
CR rate (16% vs 2%; adjusted p=0.0046), and PFS (16.7 vs 3.5 months; HR=0.270, 95% CI: 0.169, 0.430; adjusted
p<0.0001), and a reduction in patient-reported symptoms (Skindex-29 symptom domain; –27.96 vs –8.62; adjusted
p<0.0001)1,2
Safety data were consistent with the established tolerability profile1,2
1. Kim YH, et al. Blood 2016;128:182
2. Prince HM, et al. Lancet 2017;390:555–66
ALCANZA: A phase 3, randomized study comparing the efficacy and safety of
brentuximab vedotin versus physician’s choice in CD30-positive MF or pcALCL
CI, confidence interval; CR, complete response; HR, hazard ratio; IV, intravenous; ORR4, overall rate of
responses lasting ≥4 months; PFS, progression-free survival; PO, orally
Inclusion:
• Diagnosis of CD30-positive MF or
pcALCL
– ≥10% CD30-positive on either
neoplastic cells or lymphoid infiltrate
by central review of ≥1 biopsy (≥2
required for MF)
• MF patients with ≥1 prior systemic
therapy
• pcALCL patients with prior
radiotherapy or ≥1 prior systemic
therapy
Exclusion:
• Progression on both prior
methotrexate and bexarotene
Screening*
Ran
do
miz
ati
on
Methotrexate: 5–50 mg PO, weekly
or
Bexarotene: 300 mg/m² (target dose)
PO, daily
Brentuximab vedotin:
1.8 mg/kg IV, every 3 weeks
Up to 48 weeks (16 x 21-day cycles)End of
treatment
visit
Post-
treatment
follow-up
Every 12
weeks for
2 years and
then every
6 months
thereafter
30 days
after last
dose of
study drug
*Within 28 days of randomization
• Methotrexate or bexarotene was managed as standard of care, targeting maximum tolerated effective dose
• International study of 52 centers, 13 countries
ALCANZA: Key efficacy and safety data1
ALCANZA met its primary endpoint: the proportion of patients achieving an objective global response
lasting ≥4 months was 56.3% with brentuximab vedotin versus 12.5% with physician’s choice
(between-group difference = 43.8% [95% CI, 29.1–58.4; p<0.0001])
1. Prince HM, et al. Lancet 2017;390:555–66.
Maximum percentage change in skin mSWAT score PFS (assessed by independent review; ITT)
Bex, bexarotene; CI, confidence interval; ITT, intention-to-treat; mSWAT, modified Severity-
Weighted Assessment Tool; MTX, methotrexate; PFS, progression-free survival; RR, response
rate
Patient responses per IRF by baseline disease
stage/involvement (ITT population)
Treatment group
ORR4 rate
difference
(95% CI)
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR rate Total ORR4 ORR CR rate
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0 39.8 (19.9, 56.2)
Stage*
IA–IIA 15 (31) 6 (40) 8 (53) 1 (7) 18 (37) 4 (22) 5 (28) 0 17.8 (–16.6, 49.4)
IIB 19 (40) 12 (63) 13 (68) 3 (16) 19 (39) 1 (5) 3 (16) 0 57.9 (25.4, 80.9)
IIIA–IIIB 4 (8) 2 (50) 3 (75) 0 2 (4) 0 0 0 50.0 (–45.2, 98.7)
IVA 2 (4) 2 (100) 2 (100) 1 (50) 9 (18) 0 0 0 100.0 (14.9, 100)
IVB 7 (15) 2 (29) 4 (57) 0 0 NA NA NA NA
pcALCL 16 (25) 12 (75) 12 (75) 5 (31) 15 (23) 3 (20) 5 (33) 1 (7) 55.0 (19.7, 80.4)
Involvement
Skin only 9 (56) 8 (89) 8 (89) 4 (44) 11 (73) 3 (27) 5 (45) 1 (9) 61.6 (17.9, 88.3)
Extracutaneous 7 (44) 4 (57) 4 (57) 1 (14) 4 (27) 0 0 0 57.1 (–9.0, 93.2)The percentage shown in the total column describes the proportion of patients from that treatment group and the number of patients demonstrating ORR4, ORR, and CR is presented as a percentage of the figure shown
in the total column
*One patient in each arm had incomplete staging data and are not included in the table; one patient in the brentuximab vedotin arm had a PR, and one patient in the physician’s choice arm had no response
ITT, intent-to-treat; NA, not applicable
Brentuximab vedotin was superior to physician’s choice in terms of ORR4, ORR, and CR rate in MF patients across all
disease stages and in pcALCL patients with skin-only and extracutaneous disease
In both the brentuximab vedotin and physician's choice groups, the majority of patients presented with stage IA, IIA or
IIB disease and the majority of pcALCL patients presented with skin-only disease
Patient responses per IRF by baseline disease
stage/involvement (ITT population)
Treatment group
ORR4 rate
difference
(95% CI)
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR rate Total ORR4 ORR CR rate
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0 39.8 (19.9, 56.2)
Stage*
IA–IIA 15 (31) 6 (40) 8 (53) 1 (7) 18 (37) 4 (22) 5 (28) 0 17.8 (–16.6, 49.4)
IIB 19 (40) 12 (63) 13 (68) 3 (16) 19 (39) 1 (5) 3 (16) 0 57.9 (25.4, 80.9)
IIIA–IIIB 4 (8) 2 (50) 3 (75) 0 2 (4) 0 0 0 50.0 (–45.2, 98.7)
IVA 2 (4) 2 (100) 2 (100) 1 (50) 9 (18) 0 0 0 100.0 (14.9, 100)
IVB 7 (15) 2 (29) 4 (57) 0 0 NA NA NA NA
pcALCL 16 (25) 12 (75) 12 (75) 5 (31) 15 (23) 3 (20) 5 (33) 1 (7) 55.0 (19.7, 80.4)
Involvement
Skin only 9 (56) 8 (89) 8 (89) 4 (44) 11 (73) 3 (27) 5 (45) 1 (9) 61.6 (17.9, 88.3)
Extracutaneous 7 (44) 4 (57) 4 (57) 1 (14) 4 (27) 0 0 0 57.1 (–9.0, 93.2)
Brentuximab vedotin was superior to physician’s choice in terms of ORR4, ORR, and CR rate in MF patients across all
disease stages and in pcALCL patients with skin-only and extracutaneous disease
In both the brentuximab vedotin and physician's choice groups, the majority of patients presented with stage IA, IIA or
IIB disease and the majority of pcALCL patients presented with skin-only disease
Patient responses per IRF by baseline TNMB stage
per investigator: MF
For patients with MF, ORR4 and ORR were superior with brentuximab vedotin versus physician’s
choice across subgroups defined by TNMB stage
*One patient in the physician’s choice arm had no biopsy performed to confirm visceral staging, and had no response; †One patient in the brentuximab vedotin arm had incomplete staging data, and had a PR; ‡One
patient in the physician’s choice arm had confirmed blood stage B1 at screening and B2 at baseline
Treatment group
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR Total ORR4 ORR CR
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0
Skin*
T1 5 (10) 1 (20) 1 (20) 0 1 (2) 0 1 (100) 0
T2 13 (27) 7 (54) 10 (77) 1 (8) 20 (41) 4 (20) 4 (20) 0
T3 25 (52) 13 (52) 16 (64) 4 (16) 24 (49) 1 (4) 3 (13) 0
T4 5 (10) 3 (60) 4 (80) 0 4 (8) 0 0 0
Node
N0 25 (52) 14 (56) 18 (72) 4 (16) 23 (47) 2 (9) 5 (22) 0
N1–NX 23 (48) 10 (43) 13 (57) 1 (4) 26 (53) 3 (12) 3 (12) 0
Visceral*
M0 41 (85) 22 (54) 27 (66) 5 (12) 48 (98) 5 (10) 8 (17) 0
M1 7 (15) 2 (29) 4 (57) 0 0 NA NA NA
Blood†
B0 43 (90) 23 (53) 28 (65) 4 (9) 41 (84) 4 (10) 6 (15) 0
B1 4 (8) 1 (25) 2 (50) 1 (25) 7 (14) 1 (14) 2 (29) 0
B2‡ 0 NA NA NA 1 (2) 0 0 0
Patient responses per IRF by baseline TNMB stage
per investigator: MF
For patients with MF, ORR4 and ORR were superior with brentuximab vedotin versus physician’s
choice across subgroups defined by TNMB stage
*One patient in the physician’s choice arm had no biopsy performed to confirm visceral staging, and had no response; †One patient in the brentuximab vedotin arm had incomplete staging data, and had a PR; ‡One
patient in the physician’s choice arm had confirmed blood stage B1 at screening and B2 at baseline
Treatment group
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR Total ORR4 ORR CR
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0
Skin*
T1 5 (10) 1 (20) 1 (20) 0 1 (2) 0 1 (100) 0
T2 13 (27) 7 (54) 10 (77) 1 (8) 20 (41) 4 (20) 4 (20) 0
T3 25 (52) 13 (52) 16 (64) 4 (16) 24 (49) 1 (4) 3 (13) 0
T4 5 (10) 3 (60) 4 (80) 0 4 (8) 0 0 0
Node
N0 25 (52) 14 (56) 18 (72) 4 (16) 23 (47) 2 (9) 5 (22) 0
N1–NX 23 (48) 10 (43) 13 (57) 1 (4) 26 (53) 3 (12) 3 (12) 0
Visceral*
M0 41 (85) 22 (54) 27 (66) 5 (12) 48 (98) 5 (10) 8 (17) 0
M1 7 (15) 2 (29) 4 (57) 0 0 NA NA NA
Blood†
B0 43 (90) 23 (53) 28 (65) 4 (9) 41 (84) 4 (10) 6 (15) 0
B1 4 (8) 1 (25) 2 (50) 1 (25) 7 (14) 1 (14) 2 (29) 0
B2‡ 0 NA NA NA 1 (2) 0 0 0
Patient responses per IRF by baseline TNMB stage
per investigator: MF
For patients with MF, ORR4 and ORR were superior with brentuximab vedotin versus physician’s
choice across subgroups defined by TNMB stage
*One patient in the physician’s choice arm had no biopsy performed to confirm visceral staging, and had no response; †One patient in the brentuximab vedotin arm had incomplete staging data, and had a PR; ‡One
patient in the physician’s choice arm had confirmed blood stage B1 at screening and B2 at baseline
Treatment group
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR Total ORR4 ORR CR
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0
Skin*
T1 5 (10) 1 (20) 1 (20) 0 1 (2) 0 1 (100) 0
T2 13 (27) 7 (54) 10 (77) 1 (8) 20 (41) 4 (20) 4 (20) 0
T3 25 (52) 13 (52) 16 (64) 4 (16) 24 (49) 1 (4) 3 (13) 0
T4 5 (10) 3 (60) 4 (80) 0 4 (8) 0 0 0
Node
N0 25 (52) 14 (56) 18 (72) 4 (16) 23 (47) 2 (9) 5 (22) 0
N1–NX 23 (48) 10 (43) 13 (57) 1 (4) 26 (53) 3 (12) 3 (12) 0
Visceral*
M0 41 (85) 22 (54) 27 (66) 5 (12) 48 (98) 5 (10) 8 (17) 0
M1 7 (15) 2 (29) 4 (57) 0 0 NA NA NA
Blood†
B0 43 (90) 23 (53) 28 (65) 4 (9) 41 (84) 4 (10) 6 (15) 0
B1 4 (8) 1 (25) 2 (50) 1 (25) 7 (14) 1 (14) 2 (29) 0
B2‡ 0 NA NA NA 1 (2) 0 0 0
Patient responses per IRF by baseline TNMB stage
per investigator: MF
For patients with MF, ORR4 and ORR were superior with brentuximab vedotin versus physician’s
choice across subgroups defined by TNMB stage
*One patient in the physician’s choice arm had no biopsy performed to confirm visceral staging, and had no response; †One patient in the brentuximab vedotin arm had incomplete staging data, and had a PR; ‡One
patient in the physician’s choice arm had confirmed blood stage B1 at screening and B2 at baseline
Treatment group
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR Total ORR4 ORR CR
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0
Skin*
T1 5 (10) 1 (20) 1 (20) 0 1 (2) 0 1 (100) 0
T2 13 (27) 7 (54) 10 (77) 1 (8) 20 (41) 4 (20) 4 (20) 0
T3 25 (52) 13 (52) 16 (64) 4 (16) 24 (49) 1 (4) 3 (13) 0
T4 5 (10) 3 (60) 4 (80) 0 4 (8) 0 0 0
Node
N0 25 (52) 14 (56) 18 (72) 4 (16) 23 (47) 2 (9) 5 (22) 0
N1–NX 23 (48) 10 (43) 13 (57) 1 (4) 26 (53) 3 (12) 3 (12) 0
Visceral*
M0 41 (85) 22 (54) 27 (66) 5 (12) 48 (98) 5 (10) 8 (17) 0
M1 7 (15) 2 (29) 4 (57) 0 0 NA NA NA
Blood†
B0 43 (90) 23 (53) 28 (65) 4 (9) 41 (84) 4 (10) 6 (15) 0
B1 4 (8) 1 (25) 2 (50) 1 (25) 7 (14) 1 (14) 2 (29) 0
B2‡ 0 NA NA NA 1 (2) 0 0 0
Patient responses per IRF by baseline TNMB stage
per investigator: MF
For patients with MF, ORR4 and ORR were superior with brentuximab vedotin versus physician’s
choice across subgroups defined by TNMB stage
*One patient in the physician’s choice arm had no biopsy performed to confirm visceral staging, and had no response; †One patient in the brentuximab vedotin arm had incomplete staging data, and had a PR; ‡One
patient in the physician’s choice arm had confirmed blood stage B1 at screening and B2 at baseline
Treatment group
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR Total ORR4 ORR CR
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0
Skin*
T1 5 (10) 1 (20) 1 (20) 0 1 (2) 0 1 (100) 0
T2 13 (27) 7 (54) 10 (77) 1 (8) 20 (41) 4 (20) 4 (20) 0
T3 25 (52) 13 (52) 16 (64) 4 (16) 24 (49) 1 (4) 3 (13) 0
T4 5 (10) 3 (60) 4 (80) 0 4 (8) 0 0 0
Node
N0 25 (52) 14 (56) 18 (72) 4 (16) 23 (47) 2 (9) 5 (22) 0
N1–NX 23 (48) 10 (43) 13 (57) 1 (4) 26 (53) 3 (12) 3 (12) 0
Visceral*
M0 41 (85) 22 (54) 27 (66) 5 (12) 48 (98) 5 (10) 8 (17) 0
M1 7 (15) 2 (29) 4 (57) 0 0 NA NA NA
Blood†
B0 43 (90) 23 (53) 28 (65) 4 (9) 41 (84) 4 (10) 6 (15) 0
B1 4 (8) 1 (25) 2 (50) 1 (25) 7 (14) 1 (14) 2 (29) 0
B2‡ 0 NA NA NA 1 (2) 0 0 0
Patient responses per IRF by baseline TNMB stage
per investigator: MF
For patients with MF, ORR4 and ORR were superior with brentuximab vedotin versus physician’s
choice across subgroups defined by TNMB stage
*One patient in the physician’s choice arm had no biopsy performed to confirm visceral staging, and had no response; †One patient in the brentuximab vedotin arm had incomplete staging data, and had a PR; ‡One
patient in the physician’s choice arm had confirmed blood stage B1 at screening and B2 at baseline
Treatment group
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR Total ORR4 ORR CR
MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0
Skin*
T1 5 (10) 1 (20) 1 (20) 0 1 (2) 0 1 (100) 0
T2 13 (27) 7 (54) 10 (77) 1 (8) 20 (41) 4 (20) 4 (20) 0
T3 25 (52) 13 (52) 16 (64) 4 (16) 24 (49) 1 (4) 3 (13) 0
T4 5 (10) 3 (60) 4 (80) 0 4 (8) 0 0 0
Node
N0 25 (52) 14 (56) 18 (72) 4 (16) 23 (47) 2 (9) 5 (22) 0
N1–NX 23 (48) 10 (43) 13 (57) 1 (4) 26 (53) 3 (12) 3 (12) 0
Visceral*
M0 41 (85) 22 (54) 27 (66) 5 (12) 48 (98) 5 (10) 8 (17) 0
M1 7 (15) 2 (29) 4 (57) 0 0 NA NA NA
Blood†
B0 43 (90) 23 (53) 28 (65) 4 (9) 41 (84) 4 (10) 6 (15) 0
B1 4 (8) 1 (25) 2 (50) 1 (25) 7 (14) 1 (14) 2 (29) 0
B2‡ 0 NA NA NA 1 (2) 0 0 0
Patient responses per IRF by baseline TNMB stage
per investigator: pcALCL
Treatment group
Brentuximab vedotin
(N=64)
Physician’s choice
(N=64)
n (%) Total ORR4 ORR CR Total ORR4 ORR CR
pcALCL 16 (25) 12 (75) 12 (75) 5 (31) 15 (23) 3 (20) 5 (33) 1 (7)
Skin
T1 1 (6) 1 (100) 1 (100) 1 (100) 4 (27) 1 (25) 2 (50) 0
T2 3 (19) 3 (100) 3 (100) 1 (33) 5 (33) 0 1 (20) 0
T3 12 (75) 8 (67) 8 (67) 3 (25) 6 (40) 2 (33) 2 (33) 1 (17)
Node
N0 10 (63) 8 (80) 8 (80) 4 (40) 11 (73) 3 (27) 5 (45) 1 (9)
N1–NX 6 (38) 4 (67) 4 (67) 1 (17) 4 (27) 0 0 0
Visceral
M0 12 (75) 9 (75) 9 (75) 5 (42) 14 (93) 3 (21) 5 (36) 1 (7)
M1 4 (25) 3 (75) 3 (75) 0 1 (7) 0 0 0
For patients with pcALCL, ORR4 and ORR were higher with brentuximab vedotin versus physician’s
choice in patients with skin involvement, nodal involvement, and visceral involvement
Treatment group
Risk difference
(95% CI) P-value
Brentuximab
vedotin (N=64)
n (%)
Physician’s
choice (N=64)
n (%)
ORR4 39 (60.9) 5 (7.8) 53.1 (36.5, 67.2) <0.001
Best response per investigator
CR 12 (18.8) 0 18.8 (0.7, 35.9) <0.001
PR 32 (50.0) 14 (21.9) 28.1 ( – ) –
ORR 44 (68.8) 14 (21.9) 46.9 (31.7, 62.1) <0.001
SD 13 (20.3) 29 (45.3) –25.0 ( – ) –
PD 3 (4.7) 13 (20.3) –15.6 ( – ) –
updated analyses of treatment response and clinical benefit per investigator assessment after a
median follow-up of 33.9 months (data cut-off August 16, 2017)
ITT, intent-to-treat; PD, progressive disease; PR, partial response; SD, stable disease
Updated at 34 month follow up (ITT population)
Treatment group
Risk difference
(95% CI) P-value
Brentuximab
vedotin (N=64)
n (%)
Physician’s
choice (N=64)
n (%)
ORR4 39 (60.9) 5 (7.8) 53.1 (36.5, 67.2) <0.001
Best response per investigator
CR 12 (18.8) 0 18.8 (0.7, 35.9) <0.001
PR 32 (50.0) 14 (21.9) 28.1 ( – ) –
ORR 44 (68.8) 14 (21.9) 46.9 (31.7, 62.1) <0.001
SD 13 (20.3) 29 (45.3) –25.0 ( – ) –
PD 3 (4.7) 13 (20.3) –15.6 ( – ) –
updated analyses of treatment response and clinical benefit per investigator assessment after a
median follow-up of 33.9 months (data cut-off August 16, 2017)
ITT, intent-to-treat; PD, progressive disease; PR, partial response; SD, stable disease
Updated at 34 month follow up (ITT population)
Treatment group
Risk difference
(95% CI) P-value
Brentuximab
vedotin (N=64)
n (%)
Physician’s
choice (N=64)
n (%)
ORR4 39 (60.9) 5 (7.8) 53.1 (36.5, 67.2) <0.001
Best response per investigator
CR 12 (18.8) 0 18.8 (0.7, 35.9) <0.001
PR 32 (50.0) 14 (21.9) 28.1 ( – ) –
ORR 44 (68.8) 14 (21.9) 46.9 (31.7, 62.1) <0.001
SD 13 (20.3) 29 (45.3) –25.0 ( – ) –
PD 3 (4.7) 13 (20.3) –15.6 ( – ) –
updated analyses of treatment response and clinical benefit per investigator assessment after a
median follow-up of 33.9 months (data cut-off August 16, 2017)
ITT, intent-to-treat; PD, progressive disease; PR, partial response; SD, stable disease
Updated at 34 month follow up (ITT population)
Treatment group
Risk difference
(95% CI) P-value
Brentuximab
vedotin (N=64)
n (%)
Physician’s
choice (N=64)
n (%)
ORR4 39 (60.9) 5 (7.8) 53.1 (36.5, 67.2) <0.001
Best response per investigator
CR 12 (18.8) 0 18.8 (0.7, 35.9) <0.001
PR 32 (50.0) 14 (21.9) 28.1 ( – ) –
ORR 44 (68.8) 14 (21.9) 46.9 (31.7, 62.1) <0.001
SD 13 (20.3) 29 (45.3) –25.0 ( – ) –
PD 3 (4.7) 13 (20.3) –15.6 ( – ) –
updated analyses of treatment response and clinical benefit per investigator assessment after a
median follow-up of 33.9 months (data cut-off August 16, 2017)
ITT, intent-to-treat; PD, progressive disease; PR, partial response; SD, stable disease
Updated at 34 month follow up (ITT population)
Duration of response by diagnosis
DoR was much longer for patients with pcALCL receiving brentuximab vedotin (median DoR 25.5
months) than for patients with MF receiving brentuximab vedotin (median DoR 14.4 months)
Treatment group
Brentuximab vedotin (N=64) Physician’s choice (N=64)
MF
Number of patients, n (%) 48 (75) 49 (77)
Number of responders, n (%) 31 (65) 8 (16)
Median (95% CI) DoR, months 14.4 (8.5, 18.8) 18.3 (2.1, 18.4)
pcALCL
Number of patients, n (%) 16 (25) 15 (23)
Number of responders, n (%) 12 (75) 5 (33)
Median (95% CI) DoR, months 25.5 (9.5, 25.5) NE (NE, NE)
Treatment duration and follow-up status of
patients receiving brentuximab vedotin (MF and pcALCL)
SD, stable disease
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
Time (weeks)
Dis
co
ntin
ue
d tre
atm
en
t fo
r re
aso
n o
the
r th
an
PD
(n=
51
)
Each row represents one unique patient; bar length represents treatment duration; bar color shows best overall response;
black lines show response duration following end of treatment; black lines with no symbol at the end shows no PD/death at
last assessment;*Patient response was not evaluable until 120 weeks (response assessment at 120 weeks showed PD).
No response assessment
SD
CR
Time of PD
Death
PD
PR
*
Median follow-up for PFS was 33.9m
With 46 and 51 patients having progressed (39 and 46 patients) or died (7 and 5 patients), respectively, median PFS
with brentuximab vedotin versus physician’s choice was 15.8 versus 3.6 months
Kaplan-Meier estimates demonstrated improved PFS rates with brentuximab vedotin versus physician’s choice at
1 year (63.9% vs 15.6%) and 2 years (28.8% vs 8.4%)
Progression-free survival Updated at 34 month follow up (ITT)
Time to next treatment (TTNT)
At a median follow-up of 33.9 months, 47 (73%) and 48 (75%) of patients in the brentuximab vedotin and
physician’s choice arms, respectively, had received ≥1 subsequent antineoplastic therapy
Median TTNT was significantly longer with brentuximab vedotin versus physician’s choice (14.2 vs 6.1 months; HR
0.335; 95% CI, 0.218–0.515; p<0.001)
In the brentuximab vedotin versus physician’s choice arms, the probability of patients not requiring subsequent
antineoplastic therapy was greater at 1 year (65.5% vs 15.3%) and 2 years (24.6% vs 4.4%) post-randomization
Pro
ba
bili
ty o
f su
bse
qu
en
t
antin
eo
pla
stic th
era
py
PFS vs Time to next treatment (TTNT)
Median follow-up of approx 34 months
median PFS with brentuximab vedotin versus physician’s choice was 15.8 versus 3.6 months
median TTNT with brentuximab vedotin versus physician’s choice was 14.2 versus 6.1 months
PFS rates with BV versus physician’s choice at 1 year (63.9% vs 15.6%) and 2 years (28.8% vs 8.4%)
TTNT rates with BV versus physician’s choice at 1 year (65.5% vs 15.3%) and 2 years (24.6% vs 4.4%)
Why a difference
– PFS does not capture symptoms (itch, pain)
– PFS does not capture transformation – early treatment before formal PFS*
– Tempo or severity of relapse can be different – is severity of relapse on BV worse? * - longer TTNT than PFS of 3m for PC
Do we need to consider these issues in an updated “Response criteria”
Median follow-up for OS was 33.9 months, median OS was not reached in either arm; OS was not
significantly different between arms (p=0.794)
Kaplan-Meier estimates demonstrated a higher OS rate with brentuximab vedotin versus
physician’s choice at 1 year (90.4% vs 76.6%), but not at 2 years (71.1% vs 72.6%)
Overall survival
Patient-reported QoL assessed by Skindex-29 questionnaire showed significantly greater
symptom reduction for patients receiving brentuximab vedotin versus physician’s choice
(mean maximum reduction –28.08% vs –8.62%; p<0.001)
QoL per changes in symptom domain by Skindex-29 questionnaire
CD30 expression: Non-transformed mycosis fungoides with some CD30 expression
• For example, between lesions
– In patients with MF, CD30 expression can vary from lesion to lesion,13 and so can
change simply because of intrapatient variability
Challenges in CD30 detection and quantification
*In IHC, methods and techniques may vary for tissue sampling, fixation, embedding, sectioning and
mounting, antigen retrieval, primary antibody, visualisation and interpretation7
1. Wasik MA, et al. Pathobiology 2013;80:252–8; 2. von Wasielewski R, et al. Am J Pathol 1997;151:1123–30;
3. Weisenburger DD, et al. Blood 2011;117:3402–8; 4. Stacchini A, et al. Am J Clin Pathol 2007;128:854–64;
5. Hu S, et al. Blood 2013;121:2715–24; 6. Willemze R, et al. Blood 2005;105:3768–85; 7. Taylor CR, Rudbeck L (eds).
Education guide: Immunohistochemical staining methods, 6th ed. Glostrup: Dako Demark, 2013; 8. Savage KJ, et al. Blood
2008;111:5496–504; 9. Piccaluga PP, et al. J Clin Oncol 2013;31:3019–25; 10. Delabie J, et al. Blood 2011;118:148–55;
11. Kuo T-T, et al. Int J Surg Pathol 2004;12:375–87; 12. Kim YH, et al. J Clin Oncol 2015;33:3750–8; 13. Kim YH, et al.
Poster presentation at the American Society of Clinical Oncology Annual Meeting 2017; abstract 7517.
• Prognostic value of CD30 expression is unclear: study results are conflicting5,8–11
• Prognostic relevance may be subtype specific5,8,9
• CD30 expression may impact on efficacy of anti-CD30 therapy,12 although variability in
CD30 expression in patients categorised as CD30+ (≥10%) did not seem to correlate with
response13
What is the relationship
between CD30
expression and
treatment efficacy?
Can CD30
expression change?
• Critical for reliability/reproducibility1
• No consensus on what defines CD30 positivity
– Typically 10–20% of cells, but differs between studies1–5
– >75% in pcALCL and LyP (Type A and C)6
• Quantitation methods vary2–4,7*
• Issue of staining non-tumour cells; dual staining is not often used
How can measurement
of CD30 expression be
standardised?
Assessment of CD30 expression and statistical analysis
Patients with MF had ≥2 skin biopsies from separate skin lesions obtained at screening (baseline)
CD30 expression was determined using an investigational IHC diagnostic test (Ventana Medical
Systems, Inc., Tucson, AZ, USA)
Results were assessed centrally by one pathologist; patients were scored CD30-positive and
eligible for enrollment if ≥1 biopsy had ≥10% CD30-positive lymphoid cells at any intensity above
background
Of all baseline* biopsies (≥2):
– CD30min = minimum CD30 expression score; CD30max = maximum CD30 expression score
Efficacy analyses (ORR4 and PFS) were conducted for patients with MF in the brentuximab
vedotin versus physician’s choice arms by 10% cut-off to assess differences in outcome in those
with at least
1 biopsy <10% CD30-positive (CD30min <10%) versus all biopsies ≥10% CD30-positive (CD30min
≥10%)
Assessment of outcomes by CD30 expression was carried out in 100/125 eligible MF patients in
ALCANZA
*(screening) visit closest to first dose date
Assessment of CD30 expression and statistical analysis
CD30min = 10%
CD30max = 90%
CD30min ≥10%
CD30,
10%
CD30,
35%
CD30,
90%
CD30,
10%
CD30, 0%
CD30,
5%
CD30,
10%
CD30,
90%
CD30min = 0%
CD30max = 90%
CD30min <10%
ORR4 with brentuximab vedotin across a broad range
of baseline CD30 expression scores
Achieved
Not achieved
Response lasting
≥4 months (N=50)
CD30min per patientBrentuximab vedotin
n/N (%)
Physician’s choice
n/N (%)
Difference
% (95% CI)
CD30min <10% 9/22 (40.9) 2/21 (9.5) 31.4 (2.8, 58.1)
CD30min ≥10% 16/28 (57.1) 3/29 (10.3) 46.8 (20.6, 67.0)
Baselin
e C
D30 e
xpre
ssio
n,
% p
ositiv
e
0
CD30maxCD30min
10% cut-off
for enrollment10
20
30
40
50
60
70
80
90
100
MF patients who achieved ORR4
Superior PFS with brentuximab vedotin versus
physician’s choice regardless of baseline CD30 expression
Time (months) from randomization
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro
ba
bili
ty o
f P
FS
Censored
Censored
Brentuximab vedotin
Physician’s choice
Baseline CD30min <10%
Brentuximab vedotin
Physician’s choice
Baseline CD30min ≥10%
Brentuximab
vedotin
Physician’s
choiceHR (95% CI)
CD30min <10%
N 22 21 –
Median PFS
(95% CI)
27.9
(8.6, 27.9)
2.3
(1.6, 3.5)
0.125
(0.044, 0.355)
Number of events 8 17 –
CD30min ≥10%
N 28 29 –
Median PFS
(95% CI)
17.2
(9.8, NE)
3.5
(2.1, 4.6)
0.176
(0.072, 0.432)
Number of events 8 19 –
Enrolled patients with MF,
N=100
NE, not estimable
Safety profile of brentuximab vedotin
unaffected by baseline CD30 expression
AEs, n/N (%)
Brentuximab vedotin
(N=50)
Physician’s choice
(N=49)
Any AE
CD30min <10% 22/22 (100) 20/21 (95)
CD30min ≥10% 28/28 (100) 23/28 (82)
Grade ≥3
CD30min <10% 11/22 (50) 12/21 (57)
CD30min ≥10% 10/28 (36) 9/28 (32)
Serious AE
CD30min <10% 7/22 (32) 9/21 (43)
CD30min ≥10% 8/28 (29) 5/28 (18)
Peripheral neuropathy
CD30min <10% 15/22 (68) 0/21 (0)
CD30min ≥10% 19/28 (68) 2/28 (7)
Enrolled patients with MF (safety population), N=99
CD30+ transformed mycosis fungoides?
Results being analyzed
IHC images provided by HM Prince
Acknowledgments
The authors would like to thank
– the patients who participated in this study and their
families
– other investigators and staff at all ALCANZA clinical
sites
– the members of the Independent Data Monitoring
Committee and Independent Review Committee
We acknowledge
– the significant scientific contribution by Igor
Espinoza-Delgado, MD who passed away
– Matthew Hallam and Jenny Wilkinson of FireKite, an
Ashfield company, part of UDG Healthcare plc, for
writing support during the development of these
slides, which was funded by Millennium
Pharmaceuticals, Inc., and complied with Good
Publication Practice 3 ethical guidelines1
ALCANZA investigatorsAustralia: Judith Trotman, David Joske, H. Miles Prince, Kerry Taylor, Ian D. Lewis
Austria: Constanze Jonak, Franz Trautinger
Belgium: Oliver Bechter (Pascal Wolter), Dominique Bron
Brazil: Vladmir Claudio C. de Lima, Jose Antonio Sanches Junior
Canada: Richard Klasa
France: Martine Bagot, Marie Beylot-Barry, Stephane Dalle, Michel D'Incan, Brigitte Dreno,
Florent Grange
Germany: Jan Nicolay, Rudolf Stadler, Michael Weichenthal, Marion Wobser, Chalid Assaf,
Carmen Loquai
Italy: Pietro Quaglino, Michele Spina, Pier Luigi Zinzani, Alberto Bosi, Pier Paolo Fattori
Poland: Aleksandra Grzanka, Jan Walewski
Spain: Andres Lopez-Hernandez, Pablo L. Ortiz-Romero, Jose Juan Rifon Roca, Silvana
Novelli Canales
Switzerland: Reinhard Dummer
United Kingdom: Timothy Illidge, Rod Johnson, Sean Whittaker (Stephen Morris), Pam
McKay, Julia Scarisbrick
United States: Madeleine Duvic, Tatyana Feldman, Oleg Akilov (Larisa Geskin), Steve
Horwitz, Youn H. Kim, Barbara Pro (Timothy Kuzel), Adam Lerner, Herbert Eradat, Lubomir
Sokol, David C. Fisher, Sarah Hughey
1. Battisti WP, et al. Ann Intern Med 2015;163:461–4